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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1173-1176
BRIEF REPORT
Therapeutic levels of human factor VIII and IX using
HIV-1-based lentiviral vectors in mouse liver
Frank Park,
Kazuo Ohashi, and
Mark A. Kay
From the Program in Human Gene Therapy, Departments of Pediatrics
and Genetics, Stanford University, Stanford, CA 94305.
Lentiviral vectors have the potential to play an important role in
hemophilia gene therapy. The present study used human immunodeficiency virus (HIV)-based lentiviral vectors containing an EF1
enhancer/promoter driving human factors VIII (hFVIII) or IX (hFIX)
complementary DNA expression for portal vein injection into C57Bl/6
mice. Increasing doses of hFIX-expressing lentivirus resulted in a
dose-dependent, sustained increase in serum hFIX levels up to
approximately 50-60 ng/mL. Partial hepatectomy resulted in a 4- to
6-fold increase (P < 0.005) in serum hFIX of up to 350 ng/mL compared with the nonhepatectomized counterparts. The expression
of plasma hFVIII reached 30 ng/mL (15% of normal) but was transient as
the plasma levels fell concomitant with the formation of anti-hFVIII
antibodies. However, hFVIII levels were persistent in immunodeficient
C57Bl/6 scid mice, suggesting humoral immunity-limited gene
expression in immunocompetent mice. This study demonstrates that
lentiviral vectors can produce therapeutic levels of coagulation
factors in vivo, which can be enhanced with hepatocellular proliferation.
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